Adolescent major depressive disorder (MDD) is common, shows continuity with adult MDD and is associated with numerous adverse outcomes. However, biomarkers of risk for adolescent depression have remained elusive despite implications for establishing causal pathways, developing therapeutic targets, and ultimately, pre-empting adolescent MDD. Converging lines of research reveal peer rejection as a prominent trigger for adolescent MDD and neurobiological response to peer rejection as overlapping with neurobiologic deficits in MDD. Our group has shown increased neuroendocrine and fronto-amygdala response to peer rejection challenge in adolescents with MDD and at high-risk for MDD. Given increased rates of MDD and increased neurobiologic sensitivity to peer rejection in girls, we propose heightened neuroendocrine and fronto-amygdala neural response to peer rejection as a novel biobehavioral marker of MDD risk in adolescent girls. In this revised application, we investigate neuroendocrine and neural response to ecologically-valid peer rejection challenges in three groups of adolescent girls: 1) girls with current MDD, 2) girls at high risk for MDD (based on parental history), and 3) low risk control girls. The central methodology will include assessments to determine regional brain activation during a functional magnetic resonance imaging (fMRI) peer rejection task (Chatroom), and neuroendocrine response to a laboratory peer rejection task (Yale Interpersonal Stressor-Child version), "real-world" daily diary measures of social experience, and assessment of family function pubertal maturation, followed by 6 and 12-month psychiatric assessments to determine growth of depressive symptoms and onset/remission of MDD. Aims are: 1) to characterize neuroendocrine response to peer rejection in girls with MDD and at high MDD risk relative to low risk girls, 2) to characterize fronto-amygdala neural response to peer rejection in girls with MDD and at high MDD risk relative to low risk girls, 3) to characterize associations between neuroendocrine and neural response to peer rejection and explore links to "real-world" social experience, family function, and pubertal maturation, and 4) to determine if integrated neurobiological response to peer rejection distinguishes girls with MDD and at high MDD risk from low risk girls and predicts growth/remission of depressive symptoms/MDD. The revised study is the first to evaluate the neurobiological substrates of peer rejection in adolescents selected for MDD and MDD risk in a longitudinal design. Our study is distinguished by a conceptual shift of defining biomarkers in terms of contextually relevant challenges, the use of innovative, ecologically-valid methods pioneered by our group, and comprehensive, prospective measures of depression and contextual factors. Results will elucidate key and potentially modifiable processes along the pathway to MDD with implications for identifying targets and optimal developmental timing of early intervention efforts, and for developing new assessments to quantify changes in peer rejection sensitivity to evaluate treatment response and personalize treatment. PUBLIC HEALTH RELEVANCE: This application offers an innovative approach to understanding causes of depression over the adolescent transition, a key period of increased risk for depression, especially in girls. The proposed study will investigate brain and hormonal response to peer rejection as a novel mechanism underlying increased risk for depression in adolescent girls. Results will deepen our understanding of key and potentially modifiable processes along the pathway to depression that may: a) improve our ability to predict and understand adolescent depression, b) point to new assessments to quantify progression of risk and treatment response, c) lead to new medications and refinements to the content of prevention/intervention programs, and d) ultimately pre-empt adolescent depression and thus, improve life trajectories for at-risk girls.